Bronchiolitis is the leading cause of infant hospitalization in the US. Yet, its acute severity is not explained by traditional risk factors. Additionally, while infants hospitalized for bronchiolitis are at very high risk for incident asthma, little is known about the mechanisms linking these two conditions. These major knowledge gaps have hindered efforts to develop bronchiolitis treatment strategies and to prevent asthma in this high risk population. The 35th Multicenter Airway Research Collaboration (MARC-35) study (U01AI087881; Camargo, PI) is an ongoing 17-center cohort study that enrolled 1,016 hospitalized infants with bronchiolitis during 2011- 2014. In this racially-, ethnically-, and geographically-diverse cohort, investigators have collected high-quality biospecimens, including nasopharyngeal airway samples at the index hospitalization. Follow-up data include biannual parent interviews, medical record reviews, and in-person exam at age 6 years, with >90% follow-up to date. The present R01 project would extend this large well-characterized bronchiolitis cohort by profiling the gene expression of both nasopharyngeal airway microbiome (metatranscriptome) and host response (transcriptome) in the setting of bronchiolitis, and by examining their relations to both acute (bronchiolitis severity) and chronic (incident asthma) outcomes. In Aim 1, we will examine the relations among the airway microbiome profiles, host transcriptomic profiles, and acute severity of bronchiolitis. In Aim 2, we will determine the relations among the airway microbiome and host transcriptomic profiles in infants with bronchiolitis, and the risk of developing childhood asthma. Finally, using a systems biology approach, Aim 3 will define bronchiolitis endotypes by integrating clinical, virus, immunology (e.g., IgE), microbiome (composition and function) and host transcriptome data, and determine their associations with both the acute and chronic outcomes. Our pilot data lend compelling support to our hypotheses. The present R01 project will provide a unique opportunity to define the pathobiology of bronchiolitis through examining the functional activity of microbiome and host response in the airway. Furthermore, we will also determine the mechanisms linking bronchiolitis to asthma, by investigating young infants with bronchiolitis (median age, 3 months) ? a natural experiment during a critical period of lung development. The project will provide a strong evidence base for developing targeted interventions for acute bronchiolitis treatment and asthma primary prevention (e.g., through modulation of microbiome and immune responses). The investigators are NIH-funded researchers with international expertise in all relevant fields. The study matches well with the 2013 NIAID Strategic Plan.